The cGAS–STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

Oduro, Patrick Kwabena; Zheng, Xianxian; Wei, Jinna; Yang, Yanze; Wang, Yuefei; Zhang, Han; Liu, Erwei; Gao, Xiumei; Du, Mei; Wang, Qilong

doi:10.1016/j.apsb.2021.05.011

Cited by 127 publications

(73 citation statements)

References 213 publications

(324 reference statements)

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“…3 ). 305 – 309 Although the notion that obesity triggers chronic, low-grade inflammation has been recognized for decades, the pivotal role of the STING pathway in obesity has recently been appreciated. 310 – 312 The STING pathway can be activated by palmitic acid, leading to mitochondrial damage and thereby mtDNA leakage.…”

Section: Signaling Pathways In the Pathogenesis Of Obesitymentioning

confidence: 99%

Signaling pathways in obesity: mechanisms and therapeutic interventions

Wen

Zhang

et al. 2022

Sig Transduct Target Ther

147

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Obesity is a complex, chronic disease and global public health challenge. Characterized by excessive fat accumulation in the body, obesity sharply increases the risk of several diseases, such as type 2 diabetes, cardiovascular disease, and nonalcoholic fatty liver disease, and is linked to lower life expectancy. Although lifestyle intervention (diet and exercise) has remarkable effects on weight management, achieving long-term success at weight loss is extremely challenging, and the prevalence of obesity continues to rise worldwide. Over the past decades, the pathophysiology of obesity has been extensively investigated, and an increasing number of signal transduction pathways have been implicated in obesity, making it possible to fight obesity in a more effective and precise way. In this review, we summarize recent advances in the pathogenesis of obesity from both experimental and clinical studies, focusing on signaling pathways and their roles in the regulation of food intake, glucose homeostasis, adipogenesis, thermogenesis, and chronic inflammation. We also discuss the current anti-obesity drugs, as well as weight loss compounds in clinical trials, that target these signals. The evolving knowledge of signaling transduction may shed light on the future direction of obesity research, as we move into a new era of precision medicine.

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Section: Signaling Pathways In the Pathogenesis Of Obesitymentioning

confidence: 99%

Signaling pathways in obesity: mechanisms and therapeutic interventions

Wen

Zhang

et al. 2022

Sig Transduct Target Ther

147

View full text Add to dashboard Cite

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“…Accumulating pieces of evidence showed that a HFD could result in various forms of cardiac abnormalities, including cardiac inflammation, CH, and fibrosis ( Sorop et al, 2020 ; Wali et al, 2020 ; Zhang and Cai, 2020 ; Oduro et al, 2022 ); therefore, an HFD rat is an appropriate animal model for studying CH. We found that HFD rats revealed hallmarks of CH, including increased volume of cardiomyocyte size, upregulated expressions of ß -MHC and ANP ( Figure 2 ), and LV dysfunction ( Figure 3 ).…”

Section: Discussionmentioning

confidence: 99%

Metformin Attenuates Cardiac Hypertrophy Via the HIF-1α/PPAR-γ Signaling Pathway in High-Fat Diet Rats

et al. 2022

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Coronary artery disease (CAD) and cardiac hypertrophy (CH) are two main causes of ischemic heart disease. Acute CAD may lead to left ventricular hypertrophy (LVH). Long-term and sustained CH is harmful and can gradually develop into cardiac insufficiency and heart failure. It is known that metformin (Met) can alleviate CH; however, the molecular mechanism is not fully understood. Herein, we used high-fat diet (HFD) rats and H9c2 cells to induce CH and clarify the potential mechanism of Met on CH. We found that Met treatment significantly decreased the cardiomyocyte size, reduced lactate dehydrogenase (LDH) release, and downregulated the expressions of hypertrophy markers ANP, VEGF-A, and GLUT1 either in vivo or in vitro. Meanwhile, the protein levels of HIF-1α and PPAR-γ were both decreased after Met treatment, and administrations of their agonists, deferoxamine (DFO) or rosiglitazone (Ros), markedly abolished the protective effect of Met on CH. In addition, DFO treatment upregulated the expression of PPAR-γ, whereas Ros treatment did not affect the expression of HIF-1α. In conclusion, Met attenuates CH via the HIF-1α/PPAR-γ signaling pathway.

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“…They induce cell cycle checkpoint activation, transcriptional feedbacks, DNA repair, and eventually apoptosis ( 32 ). In particular, transcriptional activation of sterile inflammatory-adaptive response is a typical DDR downstream event ( 33 ). Similarly, the pathological HF transcription program is enriched for pathways related to innate immune signaling converging on NFkB/RelA, and a pro-inflammatory response converging on TGFβ signaling module, leading to cellular matrix organization ( 34 ).…”

Section: Discussionmentioning

confidence: 99%

Pressure Overload Activates DNA-Damage Response in Cardiac Stromal Cells: A Novel Mechanism Behind Heart Failure With Preserved Ejection Fraction?

Stadiotti

Santoro

Scopece

et al. 2022

Front. Cardiovasc. Med.

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Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterized by impaired left ventricular (LV) diastolic function, with normal LV ejection fraction. Aortic valve stenosis can cause an HFpEF-like syndrome by inducing sustained pressure overload (PO) and cardiac remodeling, as cardiomyocyte (CM) hypertrophy and fibrotic matrix deposition. Recently, in vivo studies linked PO maladaptive myocardial changes and DNA damage response (DDR) activation: DDR-persistent activation contributes to mouse CM hypertrophy and inflammation, promoting tissue remodeling, and HF. Despite the wide acknowledgment of the pivotal role of the stromal compartment in the fibrotic response to PO, the possible effects of DDR-persistent activation in cardiac stromal cell (C-MSC) are still unknown. Finally, this novel mechanism was not verified in human samples. This study aims to unravel the effects of PO-induced DDR on human C-MSC phenotypes. Human LV septum samples collected from severe aortic stenosis with HFpEF-like syndrome patients undergoing aortic valve surgery and healthy controls (HCs) were used both for histological tissue analyses and C-MSC isolation. PO-induced mechanical stimuli were simulated in vitro by cyclic unidirectional stretch. Interestingly, HFpEF tissue samples revealed DNA damage both in CM and C-MSC. DDR-activation markers γH2AX, pCHK1, and pCHK2 were expressed at higher levels in HFpEF total tissue than in HC. Primary C-MSC isolated from HFpEF and HC subjects and expanded in vitro confirmed the increased γH2AX and phosphorylated checkpoint protein expression, suggesting a persistent DDR response, in parallel with a higher expression of pro-fibrotic and pro-inflammatory factors respect to HC cells, hinting to a DDR-driven remodeling of HFpEF C-MSC. Pressure overload was simulated in vitro, and persistent activation of the CHK1 axis was induced in response to in vitro mechanical stretching, which also increased C-MSC secreted pro-inflammatory and pro-fibrotic molecules. Finally, fibrosis markers were reverted by the treatment with a CHK1/ATR pathway inhibitor, confirming a cause-effect relationship. In conclusion we demonstrated that, in severe aortic stenosis with HFpEF-like syndrome patients, PO induces DDR-persistent activation not only in CM but also in C-MSC. In C-MSC, DDR activation leads to inflammation and fibrosis, which can be prevented by specific DDR targeting.

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The cGAS–STING signaling in cardiovascular and metabolic diseases: Future novel target option for pharmacotherapy

Cited by 127 publications

References 213 publications

Signaling pathways in obesity: mechanisms and therapeutic interventions

Signaling pathways in obesity: mechanisms and therapeutic interventions

Metformin Attenuates Cardiac Hypertrophy Via the HIF-1α/PPAR-γ Signaling Pathway in High-Fat Diet Rats

Pressure Overload Activates DNA-Damage Response in Cardiac Stromal Cells: A Novel Mechanism Behind Heart Failure With Preserved Ejection Fraction?

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